HYPOCHOL : A Genetically-based Strategy to Identify New Targets in Cholesterol Metabolism
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 435
- 试验地点
- 2
- 主要终点
- type and number of genetic abnormalities leading to FHBL
研究概览
简要总结
The aim of this study is to identify new targets in cholesterol metabolism thanks to a genetically-based strategy.
详细描述
The goal is to recruit 400 subjects: 200 adult subjects with familial hypobetalipoproteinemia (FHBL) (index cases) plus 200 additional related subjects in at least 10 large informative FHBL families, in which there is no known mutation in FHBL genes.
The patient care is modified: patient will have an Hospital Anxiety and Depression (HAD) questionnaire (focus on depressive syndrome), a food diary, and some additional blood analysis (including genetic analysis).
One of the main issue to recruit FHBL patients is the fact that they are asymptomatic and that FHBL is not identified as a serious illness by their general physicians.
Step-1. Excluding mutations in selected candidate genes As a first approach to screen candidate genes and exclude patients with known mutations, the investigators developed a custom design based on the Haloplex™ technology (Agilent® Technologies) to perform high-throughput sequencing of the coding regions of 10 genes, including those previously described in FHBL (apolipoprotein B (APOB), Proprotein convertase subtilisin/kexin type 9 (PCSK9)), Microsomal triglyceride transfer protein (MTP or ABL), chylomicron retention disease (CMRD), Secretion associated, Ras related GTPase (SARA2 gene), as well as 6 additional candidate genes in cholesterol metabolism (low density lipoprotein receptor (LDLR), Sortilin (SORT1), Inducible Degrader of the LDL receptor (IDOL), Cholesteryl ester transfer protein (CETP), Apolipoprotein E (ApoE) and Angiopoietin-like Protein 3 (ANGTPL3)). All the recruited index cases (n=200) will be genotyped to select only those without mutations in previously described genes, being approximately 50% of our index case cohort.
Step-2. Identification of informative families and exome sequencing In patients without identified mutations, the investigators will conduct a familial screening in order to identify other cases of FHBL among proband relatives. An analysis of fasting plasma lipid parameters (total cholesterol (TC), High density lipoprotein cholesterol (HDL-C), Low-Density Lipoproteins (LDL-C) and triglycerides (TG)) will be performed for each related. Affected subjects will be determined by a spontaneous LDL-C < 80 mg/dl and/or apoB < 50 mg/dl. In contrast, non-affected subjects will display LDL-C > 80 mg/dl and/or apoB > 50 mg/dl.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For index cases without family screening:
- •o Patient with HBL: fasting LDL-C ≤ 50 mg/dl.
- •For familial affected cases:
- •Relative with HBL: fasting LDL-C ≤ 80 mg/dl and/or Apo B ≤ 50 mg/dl and at least one related family case suffering from HBL.
- •All subjects, including familial non-affected cases, must give written consent (dated and signed) to participate at the constitution of biobank (including DNA samples and urine samples).
排除标准
- •Use of lipid-lowering drugs (statins, fibrates, ezetimibe, bile-acid sequestering resin) or nutraceuticals known to affect lipids (red yeast rice, margarine and dairy with plant sterol)
- •Patient screened within an extreme metabolic disturbance (emergency situations, sepsis, hospitalization in intensive care unit)
- •Patients with hyperthyroidism, severe liver failure, end stage chronic kidney disease, serious pancreatic failure, anemia related to thalassemia or sickle cell disease, strict vegan diet or malnutrition
- •Refusal of the patient or his legal representative to participate in the study"
结局指标
主要结局
type and number of genetic abnormalities leading to FHBL
时间窗: ten years
To identify new gene involved in FHBL and determine genetic cause of FHBL (Patients with FHBL and their relatives will be recruited to establish familial forms of FHBL in large informative families with no mutations in known classical FHBL genes. This will allow perform genetic analysis using new approaches to genetic broadband (exome sequencing analysis + linkage analysis). This approach will allow specify which chromosomal regions are shared only by affected individuals, and identify new candidate genes).
次要结局
未报告次要终点